Bottom Line:
The results showed that the dissolution rate increased with increasing the ratio of polymer and surfactant to that of drug.The aqueous solubility and dissolution rate of prepared solid dispersion were significantly enhanced.Thus hot-melt extrusion (HME) is a promising technology for improving solubility and dissolution profile of ARTM.

ABSTRACTThis work studied artemether (ARTM) solid dispersion (SD) formulation using mixture of polymer excipient Soluplus, PEG 400, Lutrol F127, and Lutrol F68 melts at temperatures lower than the melting point of ARTM using a laboratory-size, single-screw rotating batch extruder. The effects of three surfactants PEG 400, Lutrol F127, and Lutrol F68 and parameters like mixing temperature, screw rotating speed, and residence time were systematically studied. SEM, XRD, and FT-IR were employed to investigate the evolution of ARTM's dissolution into the molten excipient. Differential scanning calorimetry (DSC) was used to quantitatively study the melting enthalpy evolution of the drug. The results showed that the dissolution rate increased with increasing the ratio of polymer and surfactant to that of drug. It was concluded that the dissolution of the drug in the polymer melt is a convective diffusion process and that laminar distributive mixing can significantly enhance the dissolution rate. The aqueous solubility and dissolution rate of prepared solid dispersion were significantly enhanced. In vitro antimalarial studies revealed marked improvement in IC50 values. Thus hot-melt extrusion (HME) is a promising technology for improving solubility and dissolution profile of ARTM.

Mentions:
Figures 12, 13, 14, and 15 show the dissolution profiles of various HME formulations and mixtures of ARTM with Soluplus-PEG 400, Soluplus-Lutrol F127, Soluplus-Lutrol F68, and Soluplus, respectively. Because of the extreme low solubility of the drug, 1% (w/v) SLS was added to the dissolution medium. ARTM is a poorly soluble drug with a solubility of 0.0183 μg/mL in water. The saturation solubility of the ARTM was increased (be 0.17 μg/mL) by the addition of SLS to the dissolution medium. The dissolution of the prepared HME formulations (F1 = 90.54%, F4 = 89.85%, F7 = 78.48%, F10 = 75.52%, at the end of T 20 minutes) was approximately 7.37-, 7.32-, 6.39-, 6.15-fold higher than ARTM alone at the end of T 20 minutes, respectively. The dissolution of the prepared HME formulations (F1 = 102.14%, F4 = 104.19%, F7 = 95.77%, F10 = 86.91%, at the end of T 60 minutes) was approximately 6.15-, 6.27-, 5.76-, 5.23-fold higher than ARTM alone at the end of T 60 minutes, respectively. The increase in the dissolution rate in the case of the HME formulation is attributed to the amorphous state of the drug that offers a lower thermodynamic barrier to dissolution and the formation of a glassy solution where the drug is molecularly dispersed in the polymer. The higher apparent solubility and increase in dissolution rate for amorphous materials are well known and have been extensively documented [24]. The enhancement in solubility is the result of the disordered structure of the amorphous solid. Because of the short-range intermolecular interactions in an amorphous system, no lattice energy has to be overcome, whereas in the crystalline material, the lattice has to be disrupted for the material to dissolve [25]. The solubility and dissolution rate of the drug were not enhanced by simple physical mixing with the polymer. Although SLS provided sufficient wetting of the drug particles as observed during dissolution studies, the hydrophilic polymer, Soluplus, in the physical mixture did not further enhance the dissolution of ARTM. The enhancement in dissolution in ARTM-Soluplus-PEG 400, ARTM-Soluplus-Lutrol F127 ARTM-Soluplus-Lutrol F68 and ARTM-Soluplus extrudates is also due to the conversion of crystalline drug into the amorphous state. The differences in the dissolution profile between these polymer systems are due to the solubility/dissolution nature of the polymer as well as surfactants in the dissolution medium. Dissolution of the drug in Soluplus alone is governed by the carrier, whereas in the case of Soluplus-surfactant systems, the dissolution rate is governed by solubilization of the polymer to create a hydrotropic environment for the insoluble drug. It was observed that in the dissolution studies the Soluplus-surfactant HME formulation dissolved rapidly, leaving the drug as a fine precipitate. The high-dissolution rate of ARTM from the Soluplus + PEG 400, Soluplus + Lutrol F127, and Soluplus + Lutrol F68 dispersion is believed to be due to the drug-polymer molecular intermixing at microlevel. The aqueous solubility and dissolution rate of prepared solid dispersion were significantly enhanced as shown in Figure 16.

Mentions:
Figures 12, 13, 14, and 15 show the dissolution profiles of various HME formulations and mixtures of ARTM with Soluplus-PEG 400, Soluplus-Lutrol F127, Soluplus-Lutrol F68, and Soluplus, respectively. Because of the extreme low solubility of the drug, 1% (w/v) SLS was added to the dissolution medium. ARTM is a poorly soluble drug with a solubility of 0.0183 μg/mL in water. The saturation solubility of the ARTM was increased (be 0.17 μg/mL) by the addition of SLS to the dissolution medium. The dissolution of the prepared HME formulations (F1 = 90.54%, F4 = 89.85%, F7 = 78.48%, F10 = 75.52%, at the end of T 20 minutes) was approximately 7.37-, 7.32-, 6.39-, 6.15-fold higher than ARTM alone at the end of T 20 minutes, respectively. The dissolution of the prepared HME formulations (F1 = 102.14%, F4 = 104.19%, F7 = 95.77%, F10 = 86.91%, at the end of T 60 minutes) was approximately 6.15-, 6.27-, 5.76-, 5.23-fold higher than ARTM alone at the end of T 60 minutes, respectively. The increase in the dissolution rate in the case of the HME formulation is attributed to the amorphous state of the drug that offers a lower thermodynamic barrier to dissolution and the formation of a glassy solution where the drug is molecularly dispersed in the polymer. The higher apparent solubility and increase in dissolution rate for amorphous materials are well known and have been extensively documented [24]. The enhancement in solubility is the result of the disordered structure of the amorphous solid. Because of the short-range intermolecular interactions in an amorphous system, no lattice energy has to be overcome, whereas in the crystalline material, the lattice has to be disrupted for the material to dissolve [25]. The solubility and dissolution rate of the drug were not enhanced by simple physical mixing with the polymer. Although SLS provided sufficient wetting of the drug particles as observed during dissolution studies, the hydrophilic polymer, Soluplus, in the physical mixture did not further enhance the dissolution of ARTM. The enhancement in dissolution in ARTM-Soluplus-PEG 400, ARTM-Soluplus-Lutrol F127 ARTM-Soluplus-Lutrol F68 and ARTM-Soluplus extrudates is also due to the conversion of crystalline drug into the amorphous state. The differences in the dissolution profile between these polymer systems are due to the solubility/dissolution nature of the polymer as well as surfactants in the dissolution medium. Dissolution of the drug in Soluplus alone is governed by the carrier, whereas in the case of Soluplus-surfactant systems, the dissolution rate is governed by solubilization of the polymer to create a hydrotropic environment for the insoluble drug. It was observed that in the dissolution studies the Soluplus-surfactant HME formulation dissolved rapidly, leaving the drug as a fine precipitate. The high-dissolution rate of ARTM from the Soluplus + PEG 400, Soluplus + Lutrol F127, and Soluplus + Lutrol F68 dispersion is believed to be due to the drug-polymer molecular intermixing at microlevel. The aqueous solubility and dissolution rate of prepared solid dispersion were significantly enhanced as shown in Figure 16.

Bottom Line:
The results showed that the dissolution rate increased with increasing the ratio of polymer and surfactant to that of drug.The aqueous solubility and dissolution rate of prepared solid dispersion were significantly enhanced.Thus hot-melt extrusion (HME) is a promising technology for improving solubility and dissolution profile of ARTM.

ABSTRACTThis work studied artemether (ARTM) solid dispersion (SD) formulation using mixture of polymer excipient Soluplus, PEG 400, Lutrol F127, and Lutrol F68 melts at temperatures lower than the melting point of ARTM using a laboratory-size, single-screw rotating batch extruder. The effects of three surfactants PEG 400, Lutrol F127, and Lutrol F68 and parameters like mixing temperature, screw rotating speed, and residence time were systematically studied. SEM, XRD, and FT-IR were employed to investigate the evolution of ARTM's dissolution into the molten excipient. Differential scanning calorimetry (DSC) was used to quantitatively study the melting enthalpy evolution of the drug. The results showed that the dissolution rate increased with increasing the ratio of polymer and surfactant to that of drug. It was concluded that the dissolution of the drug in the polymer melt is a convective diffusion process and that laminar distributive mixing can significantly enhance the dissolution rate. The aqueous solubility and dissolution rate of prepared solid dispersion were significantly enhanced. In vitro antimalarial studies revealed marked improvement in IC50 values. Thus hot-melt extrusion (HME) is a promising technology for improving solubility and dissolution profile of ARTM.